Lopinavir/ritonavir: A rapid review of effectiveness in COVID-19

April 14, 2020

Jienchi Dorward and Kome Gbinigie

On behalf of the Oxford COVID-19 Evidence Service Team Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences University of Oxford Correspondence to jienchi.dorward@phc.ox.ac.uk

VERDICTThere is currently no strong evidence for the efficacy of lopinavir/ritonavir in the treatment of COVID-19. Overall, the limited studies identified were subject to methodological flaws. Several ongoing trials of lopinavir/ritonavir are currenty recruiting.

BACKGROUND There are currently no pharmacological treatments for COVID-19. Due to the urgent need for effective treatments, there has been increased interest in re-purposing currently available drugs for immediate use.

The antiretroviral drug lopinavir is a protease inhibitor, which is widely used for the treatment of HIV and is a potential candidate for the treatment of COVID-19. Lopinavir is formulated in combination with another protease inhibitor, ritonavir (lopinavir/ritonavir, branded as Kaletra or Aluvia). Ritonavir inhibits the metabolising enzyme cytochrome P450 3A and therefore increases the half-life of lopinavir2.

There are some preliminary evidence of the effectiveness of lopinavir/ritonavir against other coronaviruses. In vivo, an open-label, non-randomised study found a reduced risk of severe hypoxia or death in 41 SARS-CoV patients who were treated with lopinavir/ritonavir and ribavirin, compared to 111 historical controls treated with ribavirin alone3. There has been no evidence from randomised trials of the efficacy of lopinavir/ritonavir in treating SARS-CoV or MERS-CoV.

We review the evidence for the use of lopinavir/ritonavir (LPVr) as a treatment for COVID-19.

Potential mechanism of action

The SARS-CoV-2 virus is a single-stranded RNA beta-coronavirus, similar to SARS-CoV and MERS-CoV. These viruses enter host cells and replicate, producing strands that contain multiple copies of the viral genetic material (RNA – ribonucleic acid). The strands of genetic material accumulate at the periphery of the cell, ready to be cleaved, packaged and prepared for release from the host cell4. The enzyme 3-chymotrypsin-like protease (3CLpro) plays a crucial role in processing the viral RNA5 6. As LPVr is a protease inhibitor, it may inhibit the action of 3CLpro, thereby disrupting the process of viral replication and release from host cells5 6. Recent evidence suggests that lopinavir has antiviral activity against SARS-CoV-2 in vitro7. However, coronavirus proteases, including 3CLpro, do not contain a C2-symmetric pocket, which is the target of HIV protease inhibitors, leading some to question the potential potency of HIV protease inhibitors in treating these viruses8 9. Darunavir, another HIV protease inhibitor, is reportedly not active against SARS-CoV-2 in an unpublished in vitro study10, and a recent study using in vitro and mouse models found stronger evidence for anti MERS-CoV activity for the antiviral Remdesivir compared to LPVr9.

Lopinavir/ritonavir is contraindicated in porphyria and caution is advised in patients with haemophilia, cardiac conduction disorders, pancreatitis, patients at increased risk of cardiovascular disease and those with structural heart disease11. Common side effects include gastrointestinal disturbance, in particular diarrhoea, which is often worse in the first few weeks. Dyslipidaemia, diabetes mellitus, pancreatitis and hepatic disorders have also been reported11. Drug interactions with LPVr are common due to their inhibition of cytochrome P450, which can lead to increased levels of co-administered drugs that are metabolised by this enzyme. Drugs that interact with LPVr and are commonly used in primary care include simvastatin, combined oral contraceptives, anti-epileptic drugs and inhaled fluticasone12.

Global use and price

Lopinavir/ritonavir is currently recommended by the World Health Organisation as a second-line treatment of HIV and is used by over half a million people globally 13. A two-week course costs approximately £140 (USD 170) in the UK11, and approximately £6.50 (USD 8) in certain low and middle income countries under pooled patent agreements13.

CURRENT EVIDENCE

Methods

We searched for clinical studies providing data on the efficacy of lopinavir/ritonavir for the treatment of COVID-19, restricting the search to English articles. We included pre-prints, and all clinical study designs except for case reports and case series. Systematic reviews were used as a point of reference. We also excluded articles published before 2019.

We searched PubMed, GoogleScholar, Trip and medRxiv.org on the 3rd April 2020. The search strategy used for PubMed can be found below; similar terms were used to search other sources.

We searched the reference lists of identified articles to identify further relevant articles. Title and abstract screening was conducted in detail by one review author and checked by a second author. The two authors independently performed full-text screening of identified articles. PICOS items were extracted from identified articles using a standardised form (Table 1).

We present our findings in a narrative format as the heterogeneity of outcomes and study designs made quantitative synthesis inappropriate.

RESULTS We identified 69 articles through Pubmed, 55 through medrxiv, 13 through Trip and 519 through GoogleScholar. From these, we selected 68 eligible articles through title and abstract screening, and of these articles, 35 for full-text screening. After full-text screening we included six studies in the final review (28 studies were excluded because they did not compare outcomes between patients receiving LPVr and those not receiving LPVr, and one did not provide any information about LPVr). We identified two clinical trials and four retrospective cohort studies.

Clinical trial findings

Cao et al conducted an open-label RCT at a single hospital in Wuhan, China at the peak of the epidemic14. They enrolled 199 hospitalised adults with COVID-19 pneumonia and oxygen saturations ≤ 94% on ambient air, and randomised them to receive LPVr 400mg/100mg twice a day for 14 days (n=99) or standard care (n=100). Baseline characteristics were similar between the two groups. The median age was 58 years (interquartile range [IQR] 49-68). Most patients were severely unwell and required urgent clinical attention. After 28 days, intention to treat (ITT) analysis revealed no difference in the primary outcome of time to clinical improvement between the two arms (16 days in both groups; hazard ratio 1.31; 95% CI: 0.95 to 1.85; p=0.09). Restricting the analysis to patients enrolled within 12 days of symptom onset did not alter results. When modified ITT analysis was conducted, in which three patients that died within 24 hours of randomization and did not receive LPVr were excluded, a small improvement in the time to clinical improvement was found with LPVr [median of 15 days versus 16 days, respectively; hazard ratio 1.39 (95% CI: 1.00 to 1.91)].

There was some evidence that LPVr reduced mortality at 28 days [19.2% versus 25.0%; difference – 5.8%, (95% CI, −17.3 to 5.7)], shortened ICU stays (difference -5 days; 95% CI -9 to 0), and shortened time to hospital discharge by 1 day. There was no effect of LPVr on the proportion of patients with clinical improvement at 28 days, time from randomization to death, nor duration of oxygen therapy or mechanical ventilation. There was also no difference in viral clearance between groups. Gastrointestinal symptoms were more common in the LPVr arm, and 13.8% of patients stopped treatment early due to adverse events. Overall, serious adverse events were higher in the usual care arm (32 versus 19 events), largely due to a higher frequency of acute respiratory distress syndrome (ARDS).

The ELACOI trial, a single-blind randomised controlled trial, was also performed in China15. The findings are reported in a pre-print that has not yet been peer-reviewed. The investigators initially aimed to enrol 125 adults with laboratory-confirmed SARS-CoV-2, but due to control of the epidemic, the trial was limited to 44 participants. Patients with mild or moderate clinical status (with or without signs of pneumonia) were suitable for inclusion. The mean age was 49.4 years (range 27-79). Twenty-one participants were randomised to receive LPVr for 14 days, 16 to receive Umifenovir (another antiviral) and seven to standard care with no antiviral. There was no difference in the primary outcome of time to negative pharyngeal SARS-CoV-2 PCR test between the LPVr, Umifenovir and control groups (8.5 (IQR 3-13), 7 (IQR 3-10.5) and 4 (IQR 3-10.5) days, respectively). There were no differences in pyrexia, cough or lung CT findings at 7 and 14 days. In the LPVr arm, 38.1% deteriorated to severe/critical clinical status, compared to 12.5% in the Umifenovir arm and 14.3% in the control arm (p=0.186). Five patients in the LPVr group experienced adverse events (gastrointestinal and deranged liver function), whilst no adverse events occurred in the Umifenovir or control groups.

Observational studies’ findings

We identified four observational studies that provided some empirical data for the association of Lopinavir/ritonavir with outcomes in patients with COVID-19. These studies were characterised by high levels of bias with respect to the question posed by this review. Four of these studies were pre-prints15-18 and have therefore not been peer-reviewed.

In a pre-print, Cai et al (2020)16 report outcomes from 298 patients who were hospitalised with COVID-19 at a single hospital in China between 11th January and 6th February 2020. Of these, 229 patients received LPVr, 30 received favipiravir (another antiviral agent) and 39 received no antiviral treatment. No patients died, and 10.7% were admitted to intensive care. The authors report that there was no difference in time to viral clearance amongst those who received LPVr or favipiravir (15 days, IQR 10-19) versus those who did not receive antiviral therapy (14 days, IQR 10-19).

Hu et al (2020)17 conducted a retrospective review of 323 patients hospitalised with COVID-19 at Tianyou Hospital between 8th January and 20th February 2020. Patients were categorized into non-severe (n= 151), severe (n = 146) and critical (n=26) based on the clinical presentation at the time of admission. Univariate analysis revealed that amongst patients receiving LPVr (n=28) a higher proportion developed unfavourable outcomes, including death or disease progression (23.8% versus 5%, p<0.001), compared to those not on LPVr (n=295). However, patients with critical disease severity at baseline were more likely to receive LPVr compared with those with non-severe and severe disease (p<0.001), meaning that the worse outcomes amongst those receiving LPVr could be explained by bias.

Zhou and colleagues (2020)19 conducted a retrospective, multicentre cohort study including all adult inpatients with laboratory confirmed COVID-19 from Jinyintan Hospital (n=135) and Wuhan Pulmonary Hospital (n=56) who had been discharged or had died by January 31st 2020. Of the 29 patients who received LPVr and survived, the median duration of virus shedding was 22 days (IQR 18-24), compared with 20 days (IQR 17-24) in survivors in the entire study population. However, patients receiving LPVr would also have been counted in the entire study population, making it difficult to determine the meaningfulness of this comparison.

A further retrospective study of 120 hospitalised SARS-CoV-2 patients, but not critically ill, assessed risk factors associated with viral shedding18. The authors conducted multivariate logistic regression to determine the factors that are associated with prolonged viral shedding longer than 23 days. When adjusting for age and sex, they found that not being treated with LPVr was associated with significantly increased odds of prolonged viral shedding (adjusted odds ratio 2.42; 95% CI 1.10 – 5.36; p=0.03). They also found that patients who started LPVr within 10 days of symptom onset had a shorter duration of viral shedding than patients that started treatment later (median 19 days versus 27.5 days respectively, p < 0.001). However, no significant difference in the median duration of viral shedding was found between patients who initiated LPVr treatment more than 10 days after symptom onset and those not receiving LPVr (median 27.5 days versus 28.5 days, p=0.86). The authors, therefore, suggest that treatment with Lopinavir/Ritonavir within 10 days of symptom onset could shorten the duration of viral shedding. The authors report that those receiving LPVr were more likely to be categorized as severe COVID-19, however, the analyses were not adjusted for COVID-19 severity. This could, therefore, be a source of bias.

Comparison with existing literature

We identified one systematic review assessing the efficacy and safety of antiretrovirals against coronaviruses including SARS-CoV-220. They identified one of the two RCTs identified in this rapid review14, seven cohort studies, one case series and three case reports assessing the use of LPVr in treating COVID-19. Of the seven cohort studies, five did not provide comparative data assessing patients who did and did not receive LPVr, one study was in the Chinese language, and one study has been temporarily removed when viewed online. Our rapid review, containing one new RCT and four new observational studies, therefore provides an important update.

Limitations of the current evidence

The evidence that we have identified comes from a limited number of studies (n=6), some with small numbers of participants (range: 44 – 323). Four of the six identified studies are pre-prints, and therefore have not been peer-reviewed. Only two of the identified studies are randomised clinical trials; after systematic reviews, well-conducted randomised clinical trials provide the second highest level of evidence21. Neither of the trials was double-blinded, and the ELACOI trial was underpowered.

Observational studies, by virtue of their design, are more susceptible to bias. Only one of the observational studies adjusted for potential confounders using multivariate analyses18, although they did not adjust the results for COVID-19 severity, despite the fact that patients receiving LPVr were more likely to be categorized as having severe COVID-19. Lack of adjustment of results for important co-variates can produce misleading results.

CONCLUSIONS We identified only two randomised clinical trials assessing the utility of LPVr in treating COVID-19. Both of these studies suffer with methodological problems, including lack of blinding and small sample sizes. Neither study reported a benefit from LPVr with regard to their primary outcomes of time to clinical improvement and negative pharyngeal SARS-CoV-2 PCR test.

In terms of secondary outcomes, there was some evidence that LPVr may have reduced mortality at 28 days, and shortened ICU admissions and time to discharge. Gastrointestinal side effects were more common in patients treated with LPVr. However, due to the above-mentioned limitations, these findings must be treated with great caution. There were mixed findings of an association of LPVr treatment with shortening the duration of viral shedding amongst the identified observational studies.

At present, there is insufficient evidence to recommend the use of LPVr for COVID-19 outside of research studies. In order to determine the efficacy and safety of LPVr for COVID-19, more adequately powered randomised clinical trials of LPVr for COVID-19 are required. Ideally, these studies should be double-blinded and conducted in a range of settings (we did not identify any studies conducted in primary care where patients are likely to present earlier). Rigorous reporting of adverse events is critical, especially as there is an indication from both trials that gastrointestinal side effects are more common with LPVr treatment compared with usual care. If there is a positive signal from further studies, these should help to determine the optimal dose and duration of treatment.

Disclaimer: the article has not been peer-reviewed; it should not replace individual clinical judgement and the sources cited should be checked. The views expressed in this commentary represent the views of the authors and not necessarily those of the host institution, the NHS, the NIHR, or the Department of Health and Social Care. The views are not a substitute for professional medical advice.

BIO

Jienchi Dorward* and Kome Gbinigie* are both General Practitioners and doctoral researchers based at the Nuffield Department of Primary Care Health Sciences, University of Oxford

*Co-first authors for this CEBM review

SEARCH TERMS

PubMed:

(coronavirus*[Title] OR coronovirus*[Title] OR coronoravirus*[Title] OR coronaravirus*[Title] OR corono-virus*[Title] OR corona-virus*[Title] OR “Coronavirus”[Mesh] OR “Coronavirus Infections”[Mesh] OR “Wuhan coronavirus” [Supplementary Concept] OR “Severe Acute Respiratory Syndrome Coronavirus 2″[Supplementary Concept] OR COVID-19[All Fields] OR CORVID-19[All Fields] OR “2019nCoV”[All Fields] OR “2019-nCoV”[All Fields] OR WN-CoV[All Fields] OR nCoV[All Fields] OR “SARS-CoV-2”[All Fields] OR HCoV-19[All Fields] OR “novel coronavirus”[All Fields]) AND (Kaletra OR Lopinavir* OR Alluvia OR LPV*).

GoogleScholar:

(coronavirus OR covid-19 OR 2019nCoV OR 2019-nCov oR WN-cov OR nCoV OR SARS-CoV-2 OR HCov-19) AND (Kaletra OR Lopinavir* OR Alluvia OR LPV*).